Visceral pain is usually caused by excessive dilation of internal organs, necrosis of these cells or intensive contraction or acute relaxation of internal organs. When there is a tumor, infection or congestion in internal organs, slight mechanical stimulus, acidic or basic solution might cause severe pain. Visceral pain caused especially by tumors cannot be easily suppressed even with an excessive amount of morphine, so neuro-surgical operations such as partial myelotomy of the spinal cord are frequently used (Gybels, Pain Headache, 1989, 11:1-402). However, the bilateral cordotomies or commissural myelotomies of spinothalamic tract have many side effects. Relatively, the midline myelotomy that severs the upper middle part of the T10 spinal cord is known as an effective remedy (Nauta, J. Neurosurg., 1997, 86:538-542).
The above result proves that the visceral pain signal is delivered to the brain through the spinal cord, which supports the fact that the visceral pain signal is delivered through a different channel from other pains. According to a MRI test carried out on a-visceral-pain-induced monkey, it can be known that visceral pain induces the activation of thalamus (Willis, Proc. Natl. Acad. Sci. USA., 1999, 96:7675-79). The result of the test, after all, tells that the visceral pain is delivered from the pain sensory cells in the end of the internal organs through the spinal cord to thalamus. Particularly, thalamus is known as an important sensory processing organ since it delivers the stimulus to the cerebral cortex (McCormick, Curr. Opin. Neurobiol., 1994, 4:550-556).
The calcium in nerve cells plays an important role in delivering signals between nerve cells. Calcium has many different delivery paths, however, when delivering peripheral stimuli, the voltage-activated calcium channel is crucial. The voltage-activated calcium channel can be categorized into the high voltage-activated calcium channel (HVA) that is activated at a higher voltage than the resting membrane potential and the low voltage-activated calcium channel (LVA) that is activated at a lower voltage. The HVA calcium channel can be subdivided into L, P/Q, N or R-type depending on the pharmacological property of the current, and the LVA calcium channel is differentiated as T-type (Tsien, Trends Neurosci., 1988, 11:431-438).
The HVA calcium channel is evenly expressed from the peripheral sensory cells to the central nervous system, and is well known to play an important role in transmission of the sense of pain and reflection. The inhibitors against these channels are already commercially available as various anodynes (Schaible, Prog. Brain Res., 2000, 129:173-190). However, it is not yet clearly understood how the LVA calcium channel that generates the T-type calcium current can regulate pain. The reason why the T-type calcium current is categorized as one of the functions of the LVA calcium channel is that when the excitability of nerve cells lowers, the calcium current are generated so that the excitability increases again (Llinas, J. Physiol (Lond), 1981, 315:549-567; McCormick, Neuroscience, 1990, 39:103-113). Thus, the nerve cells excited by the T-type calcium channel have the property of burst firings and induce a type of excitability different from tonic firings (Llinas, J. Physiol (Lond), 1981, 315:549-567). The channel protein of the T-type calcium channel is encoded by three different genes, which are referred to as alpha1G, alpha1H and alpha1I respectively (Perez-Reyes, Nature, 1998, 391:896-900). It is known that the alpha1G and alpha1H T-type calcium channels are expressed in the back of the spinal cord, and that the alpha1G is expressed in thalamocortical relay neurons (Talley, J. Neurosci., 1999, 19:1895-1911), and that is identical with the delivery path of the visceral pain. Recently, it has been proved in an experiment using a T-type calcium current inhibitor, mibefradil, that the function of the T-type calcium current in the peripheral nerves is related to hyperalgesic reaction against thermo-stimuli or mechanical stimuli by reducing agents (Todorovic, Neuron, 2001, 31:75-85), however, it has not yet been found which T-type calcium channel is related. Mibefradil (RO40-5967) was initially known for lowering blood pressure (Clozel, Cardiovasc Drugs Ther., 1990, 4:731-736; Hefti, Arzneimittelforschung, 1990, 40:417-421), and was reported to have a suppression effect (Viana, Cell Calcium, 1997, 22:299-311). Recently, it has been reported that Mibetradil has the most selective suppression effect on T-type calcium channels.
Thus, the present inventors have studied about visceral pain with alpha1G−/− transgenic mice and found that the alpha1G−/− transgenic mice show hyperalgesia to visceral pain caused by acetic acid. In wild-type mice, visceral pain caused by acetic acid could be alleviated by administration of mibefradil at the periphery but enhanced when mibefradil is injected in the brain. The present invention has been accomplished by confirming that visceral pain can be modulated by controlling the T-type calcium channel.